tbuckley/cabot-search huggingface dataset:
Abstract 5943: Association between the consumption of meat and carbonated drinks and early onset gastric cancer in Chilean patients
Authors: Carol Parra, Graciela Molina, Carla Coo, Jessica López, María San Martín, Javiera Siche, Luis Carvajal-Carmona
Journal: Cancer Research (2022)

Abstract Gastric cancer (GC) is the 5th most frequent neoplasm and the 3rd cancer with the highest mortality according to GLOBOCAN. GC is often diagnosed in middle aged and elderly people, with a peak in incidence between 60 and 70 years old. In contrast, early-onset GC is the GC had a strong hereditary component. Associations of sporadic late onset-GC and dietary factors have been published but the role of nutritional factors in early onset GC is unknown. The aim of this study is to investigate the association between the intake of red meat, pork, processed meats and carbonated drinks in a group of early-onset GC. Our study was carried out in 19 Chilean early-onset GC patients, aged between 32 and 60 years, and 32 healthy age matched individuals from the same population. Through a survey of nutritional habits carried out retrospectively considering the stage prior to the diagnosis of GC, we determined the amount, type and frequency of ingestion of red meat, pork, processed meat and carbonated beverages. To measure the association an odds ratio and non-parametric association statistic tests were used. For the association of meat intake, we used the WHO recommendation (less than 70 g of meat per day) to classify the meat consumption levels in both groups. An odds ratio of 25.5 (4.8-135.4, p=8.3x105) was determined between the consumption of more than 70 g of meat per day in the early onset GC group vs the control group. Even though there are no international recommendations for carbonated drinks consumption levels, we found a higher carbonated drink consumption among cases (cases: Ave.= 180,7, SD= ±108,5 vs controls: Ave.=43,3, SD=±38,3. P=0033). In conclusion, our results shows significant associations between the consumption of red meat, pork, processed meats, and carbonated drinks in the risk of early-onset GC patients compared with the control group. Our findings, suggest that nutritional factors could play a role in the early GC presentation, acting in conjunction with low penetrance gene mutations. We will incorporate more early onset patients to the study group and do a sex matching for the control group to evaluate this possible confounding factor. We will also incorporate a late onset GC group. We think that nutritional factors could be an important factor to modulate genetic risk, even in early-onset patients. Beca Chile Postdoctorado 74190063 to GM. Citation Format: Carol Parra, Graciela Molina, Carla Coo, Jessica López, María San Martín, Javiera Siche, Luis Carvajal-Carmona. Association between the consumption of meat and carbonated drinks and early onset gastric cancer in Chilean patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5943.
Abstract 1679: Single-cell profiling reveals a conserved myogenic hierarchy in pediatric rhabdomyosarcomas amenable to differentiation therapy
Authors: Sara G. Danielli, Ermelinda Porpiglia, Andrea J. De Micheli, Ingrid Bechtold, Joana G. Marques, Stephanie Kasper, Helen M. Blau, Marco Wachtel, Beat W. Schäfer
Journal: Cancer Research (2022)

Abstract Rhabdomyosarcoma (RMS) is a highly aggressive pediatric soft tissue cancer, associated with the skeletal muscle lineage. Despite undoubted expression of key myogenic regulatory factors, RMS cells are blocked in a proliferative state and do not complete terminal differentiation. The extent to which the skeletal muscle lineage is represented in RMS tumors, as well as the mechanisms leading to developmental arrest, remain elusive. We therefore aimed to identify RMS subpopulations, understand why RMS cells are stalled in their differentiation path, and determine mechanisms to pharmacologically restore myogenic differentiation. Using single-cell RNA sequencing and mass cytometry analysis, we profiled cells from 14 PDX-derived primary cultures and three cell lines of alveolar (aRMS) and embryonal RMS (eRMS) subtypes. We discovered that both RMS subtypes contain different cell subpopulations distributed along the myogenic lineage. aRMS tumors recapitulate a yet unrecognized branched myogenic trajectory, where progenitor cells either commit to differentiation or give rise to actively cycling myoblasts. Following in vitro exposure to chemotherapy, aRMS cells show compositional shifts towards undifferentiated states, consistent with a model where treatment rewires cellular trajectories. To quantify aRMS cellular states, we developed an automated image-based single-cell approach and applied it to identify pro-differentiating agents among a library of &amp;gt;240 FDA-approved drugs. We identified the RAS pathway as an important mediator of myogenic differentiation in several aRMS cultures, demonstrating the potential for differentiation therapy. Current studies are ongoing to validate these results in vivo and to uncover drug combinations that completely overcome the differentiation block. Taken together, this study reveals possible cellular origins for RMS and identifies a potential novel treatment strategy for aRMS that targets cellular differentiation. Citation Format: Sara G. Danielli, Ermelinda Porpiglia, Andrea J. De Micheli, Ingrid Bechtold, Joana G. Marques, Stephanie Kasper, Helen M. Blau, Marco Wachtel, Beat W. Schäfer. Single-cell profiling reveals a conserved myogenic hierarchy in pediatric rhabdomyosarcomas amenable to differentiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1679.
Abstract 6030: <i>Reconstructed Pancreas</i>: A tumor-specific 3D culture platform for accurate evaluation of therapeutic agents in pancreatic cancer
Authors: Eleanore J. Kirshner, Aayushi Ahlawat, Matthew Ryou
Journal: Cancer Research (2022)

Abstract As it is rarely diagnosed early, the prognosis for patients with pancreatic cancer is grim. The average 5-year survival rate is 10% and only 3% for patients with metastatic disease. Partially because of the late diagnosis and partially because of its biology, treatment options for patients with pancreatic cancer are limited and new interventions are desperately needed to gain the upper hand on this disease. One of the challenges faced by the drug developers looking for agents against pancreatic cancer is capturing the elements of the tumor microenvironment, which provides both a physical barrier and stroma-driven resistance to therapeutic agents. We developed a tumor-specific Reconstructed Pancreas (r-Pancreas) model, which recapitulates the cellular and extracellular elements of the pancreatic tumor microenvironment. In the r-Pancreas model, tumor and stromal cells are embedded in a dense extracellular matrix (ECM) characteristic of pancreatic tumors. Pancreatic tumor cell lines, MiaPaca-2, Panc-1, and Bx-PC3 robustly proliferate and survive for 14 days providing an extended therapeutic window to test anti-tumor compounds in the context of pancreas-specific ECM. Mimicking clinical response pancreatic tumor cells grown in r-Pancreas are sensitive to gemcitabine (IC50=0.4-0.6µM) but are resistant to 5-fluorouracil (IC50=not reached). These cell lines were also 5-10 times less sensitive to gemcitabine when cultured in Matrigel (IC50=3-6µM), soft ECM rich in collagen IV/laminin neither of which is abundant in the pancreas. Incorporating a collagen-rich capsule into the r-Pancreas model further expands its physiological relevance as human pancreatic tumors have been shown to have an outer layer of stiff ECM, which provides a physical barrier that impedes drug access to the tumor. Finally, establishing a co-culture of pancreatic tumor cell lines with primary pancreatic stromal cells creates a complete model enabling testing of novel therapeutic agents within the pancreatic tumor microenvironment. Taken together these data suggest that to be clinically useful in vitro tumor models not only need to allow for 3-dimensional cell growth but also have to incorporate tumor-specific elements of the microenvironment. Citation Format: Eleanore J. Kirshner, Aayushi Ahlawat, Matthew Ryou. Reconstructed Pancreas: A tumor-specific 3D culture platform for accurate evaluation of therapeutic agents in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6030.
Abstract CT502: Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma
Authors: Rom S. Leidner, Matthew H. Taylor, Tarsem L. Moudgil, Tanisha L. Christie, Yoshinobu Koguchi, Alexa Dowdell, William L. Redmond, Shawn M. Jensen, Carmen Ballesteros-Merino, Jake A. Vancampen, Venkatesh Rajamanickam, Brady M. Bernard, Christopher Paustian, Traci L. Hilton, Hong-Ming Hu, Richard B. Bell, Walter J. Urba, Carlo B. Bifulco, Brian Piening, Bernard A. Fox
Journal: Cancer Research (2022)

Abstract Background: Preclinical studies document that complex cancer vaccines, combined with T cell agonists and anti-PD-1, can augment therapeutic efficacy. Here we report preliminary immunological analyses of patients enrolled in a first-in-human immunotherapy-trio study of multivalent autophagosome vaccine (DPV-001), with sequenced checkpoint inhibition (anti-PD-1; retifanlimab), with/without anti-GITR agonist (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024). Methods: Peripheral blood (PB) and sera are collected regularly and PB are evaluated by flow cytometry. Biopsies obtained at baseline, D15 and D45 are analyzed by multiplex IF and 10x Genomics scRNA-Seq. Sera are being analyzed by phage immunoprecipitation (PhIP) sequencing for reactivity against the human proteome. Results: Preliminary results document increases in activated CD4 and CD8 effector memory T cells (TEM) with vaccine alone. Changes in tumor microenvironment (TEM) were also observed with increased infiltration of immune cells. Evaluation of changes to humoral immunity, T cell function and TCR analyses are ongoing. Conclusions: We previously reported immunological monitoring of a phase I/II trial of an autophagosome cancer vaccine (DPV-001) containing more than 300 shared cancer antigens, as adjuvant therapy for NSCLC. Vaccination induced or augmented immune responses to more than 50 cancer antigens shared with head and neck squamous cell carcinoma (HNSCC). Preclinical studies combining this cancer vaccine with αGITR agonist and αPD-1 augmented therapeutic efficacy [PMID: 31747946], and provided the rationale for the current study. This is the first clinical trial to perform such a study with αGITR agonist (INCAGN-1949), in humans. Support: Incyte, Providence Medical Foundation, The Harder Family, Nancy Lematta. Citation Format: Rom S. Leidner, Matthew H. Taylor, Tarsem L. Moudgil, Tanisha L. Christie, Yoshinobu Koguchi, Alexa Dowdell, William L. Redmond, Shawn M. Jensen, Carmen Ballesteros-Merino, Jake A. Vancampen, Venkatesh Rajamanickam, Brady M. Bernard, Christopher Paustian, Traci L. Hilton, Hong-Ming Hu, Richard B. Bell, Walter J. Urba, Carlo B. Bifulco, Brian Piening, Bernard A. Fox. Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT502.
Abstract 5778: Early age of onset of double germline DDR-mutated gastric cancer
Authors: Yurong Qu, Min Shi, Yiming Liang, Bowen Zhu
Journal: Cancer Research (2022)

Abstract Background: Gastric cancer (GC) is one of the leading causes of cancer death in China. Approximately 10% of GC cases are associated with strong familial clustering and can be attributed to genetic predisposition. However, GC is biologically and genetically highly heterogeneous, the underlying genetic cause is complicated. DNA damage repair (DDR) genes play key roles in maintaining human genomic stability. Loss of DDR function, conversely, is an important determinant of cancer risk, progression, and therapeutic response.Our aim was to analyze the germline mutational pattern of DDR-mutated Chinese GC cohort and find possible genetic factors related to the early onset of gastric cancer. Methods: In this analysis we defined a “core DDR” gene set with 10 homologous recombination deficiency-HRD gene (BRCA1, BRCA2, ATM, PALB2, BRIP1, CDK12,CHEK1, CHEK2,FANCA and FANCL) and 4 mismatch repair-MMR gene (MLH1,MSH2,PMS2 and PMS6). The panel of 14 core DDR genes was used to analyze the germline mutation profiling of DDR-mutated GC cohort which is consisted of 144 Chinese patients with at least one germline “core DDR” gene likely pathogenic/pathogenic (LP/P) mutations. LP/P mutations were called according to the classification criteria of the American College of Medical Genetics and Genomics. Results: The DDR-mutated GC cohort was consist with 144 patients with at least one “core DDR” gene germline mutations, and the median age of this cohort was 63 years. In this cohort, eighty-three of 144 patients carried only one HRD gene P/LP mutations (median age at onset:63), forty-two patients of 144 patients carried only one MMR gene P/LP mutation (median age at onset:65.5). Nineteen of 144 (13.2%) patients had two “core DDR” germline mutation, and the median age of these patients with double germline mutations was 49. The double DDR-mutated GC had a significantly younger median age of onset than one HRD-mutated GC (log-rank test, P =0.00746) as well as one MMR-mutated GC (log-rank test, P =0.00849). Three of the double DDR-mutated patients had family histories of gastrointestinal cancer. Conclusion: Our data suggests that GC patients harboring any two germline mutations in the “core DDR” gene may have an earlier age of onset. Citation Format: Yurong Qu, Min Shi, Yiming Liang, Bowen Zhu. Early age of onset of double germline DDR-mutated gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5778.
Abstract 2677: JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models
Authors: Robert Hauptschein, Simon Woodcock, Andrew Belfield, Helen Mason, Dorottya Keppel, Svetlana Markova, Kyuri Kim, Shane Roller, Caroline Phillips, Clifford D. Jones, Robin C. Humphreys
Journal: Cancer Research (2022)

Abstract Activation of the mitogen-activated protein kinase (MAPK) pathway by oncogenic mutations in RAS and RAF is a frequent driver of human cancer. Targeting specific components of the pathway is a precise and rational route to deliver benefits to cancer patients with high unmet therapeutic needs. The RAF kinase proteins (ARAF, BRAF, CRAF) are core pathway components which mediate MAPK signaling. Mutations in these critical signaling proteins leads to constitutive activation of the MAPK pathway and tumor growth. Using state of the art screening methodologies and medicinal chemistry we discovered and developed a next generation pan-RAF kinase inhibitor, JZP815, which potently inhibits wild-type and mutant RAF kinases in cell-free and cell-based assays. JZP815 is a selective RAF kinase inhibitor that suppresses all 3 RAF kinase family members at low-to-sub nanomolar potencies in cell-free assays. Moreover, in tumor cells JZP815 does not induce significant paradoxical pathway activation, observed with approved 1st generation BRAF-selective inhibitors, while demonstrating equivalent potencies for MAPK pathway inhibition driven by either mutant RAF monomers or RAS-induced RAF dimers in tumor cells. JZP815 significantly inhibited tumor growth as a single agent in multiple mouse xenograft solid tumor models harboring RAS and/or BRAF mutations. Furthermore, JZP815’s favorable pharmacokinetic profile sustained on-target pathway pharmacodynamic responses in a predictable dose and time dependent manner. JZP815 demonstrated enhanced activity when combined with inhibitors of other MAPK pathway components in both class 2 and class 3 mutant BRAF patient-derived tumor cells ex vivo, and KRAS mutant NSCLC and CRC xenografts in vivo. In summary, JZP815 is a potent and selective pan-RAF inhibitor that is orally bioavailable in multiple preclinical species with a well-behaved safety profile and pharmacokinetic properties predicted to provide drug exposure required for target engagement in humans, and therefore suitable for advancing into first-in-human trials. Citation Format: Robert Hauptschein, Simon Woodcock, Andrew Belfield, Helen Mason, Dorottya Keppel, Svetlana Markova, Kyuri Kim, Shane Roller, Caroline Phillips, Clifford D. Jones, Robin C. Humphreys. JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2677.
Abstract 2857: DR30303, a SMART-VHHBody powered anti-CLDN18.2 VHH-Fc with enhanced ADCC activity for the treatment of gastric and pancreatic cancers
Authors: Yongliang Fang, Gaofeng Yao, Weixiang Zhong, Wenwen Duan, Zhenxing Zhou, Xiaofang Wen, Yonglu Chen, Jingjin Fang, Yongwei Wang, Weiqin Jiang, Junfang Xu, Yanshan Huang
Journal: Cancer Research (2022)

Abstract Claudin 18.2 (CLDN18.2) is aberrantly overexpressed in gastric cancer, pancreatic adenocarcinomas, and a fraction of non-small cell lung cancer. Its tumor specificity allows CLDN18.2 to be an attractive target for developing biotherapeutics for the treatment of gastric and pancreatic cancers. DR30303 is a humanized ant-CLDN18.2 heavy chain antibody Fc fusion protein (VHH-Fc) generated via Doer Biologics’ proprietary SMART-VHHBody platform. DR30303 exhibits strong and highly selective binding to CLDN18.2, but not its close splicing variant CLDN18.1. In addition, it exhibits enhanced ADCC activity as a result of Fc engineering and low immunogenicity risk validated via in-silico T-cell epitope predictor. Its smaller size (78 kDa vs 150 kDa for conventional full-length IgG) allows DR30303 to penetrate solid tumors faster and deeper, resulting in a strong competitive advantage and differentiation compared with other anti-CLDN18.2 antibodies in the market. Single-agent therapeutic potency of DR30303 was demonstrated in various gastric and pancreatic cell-derived xenograft (CDX) mouse models with a minimum effective dose of 0.3 mg/kg dose of DR30303 led to TGI≥90%, which is significantly more potent (p&amp;lt;0.05) than the benchmark reference Zolbetuximab analog in same molar ratio. Moreover, DR30303 showed strong synergistic anti-tumor activities with paclitaxel, gemcitabine, and EOF (epirubicin, oxaliplatin, and fluorouracil) in patient-derived xenograft (PDX) mouse models (gastric cancer) and CDX model (pancreatic cancer). DR30303 also demonstrated favorable pharmacokinetic properties (t1/2~ 120 hours) and tolerable toxicities (MTD≥ 748.5 mg) in both SD rats and cynomolgus monkeys. Doer Biologics submitted IND to the NMPA in November 2021 and plans to initiate the Phase 1 clinical trial in H1 2022 upon IND approval. Citation Format: Yongliang Fang, Gaofeng Yao, Weixiang Zhong, Wenwen Duan, Zhenxing Zhou, Xiaofang Wen, Yonglu Chen, Jingjin Fang, Yongwei Wang, Weiqin Jiang, Junfang Xu, Yanshan Huang. DR30303, a SMART-VHHBody powered anti-CLDN18.2 VHH-Fc with enhanced ADCC activity for the treatment of gastric and pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2857.
Abstract 1545: The cytostatic effect of miR-3189-3p in triple negative breast cancer cells involves inhibition of mitochondrial-mediated apoptosis
Authors: Cecilia Vittori, Hassan Yousefi, Krzysztof Reiss, Francesca Peruzzi
Journal: Cancer Research (2022)

Abstract Our laboratory has previously characterized a microRNA, miR-3189-3p, with potent anti-cancer activity against glioblastoma and triple negative breast cancer (TNBC), two of the most aggressive types of tumors. Intriguingly, while miR-3189-3p inhibits proliferation, migration, and invasion of glioblastoma and TNBC cells, it does not induce apoptosis. The BCL2 family of proteins controls mitochondrial-mediated cell death through binding affinity and abundance of pro- and anti-apoptotic factors. Here, we investigated the mechanisms of the cytostatic effect of miR-3189-3p on MDA-MB-231 cells and found that the BCL2-family members and pro-apoptotic factors BAK1, BMF, and HRK, which are predicted gene target of this miRNA, are indeed downregulated by the miRNA mimic. In addition, we found that expression of miR-3189-3p improved the metabolic fitness of TNBC cells through increasing both mitochondrial respiration and glycolysis. Ongoing experiments are aimed at understanding how changes in the metabolic profile and cytostatic activity of miR-3189-3p could be used for therapeutic intervention against this aggressive tumor. Citation Format: Cecilia Vittori, Hassan Yousefi, Krzysztof Reiss, Francesca Peruzzi. The cytostatic effect of miR-3189-3p in triple negative breast cancer cells involves inhibition of mitochondrial-mediated apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1545.
Abstract 513: Radiomic profiles revealing targets for therapy in cervical cancer
Authors: Mari Kyllesø Halle, Erlend Hodneland, Erling Hoivik, Kari Wagner-Larsen, Njål G. Lura, Julie Dybvik, David Forsse, Bjørn I. Bertelsen, Camilla Krakstad, Ingfrid S. Haldorsen, Olivera Bozickovic, Kathrine Woie
Journal: Cancer Research (2022)

Abstract Magnetic resonance imaging (MRI) has emerged as an important part of the diagnostic work-up in cervical cancer, with tumor volume and extent as important prognosticators. MRI radiomic tumor features may aid in prognostication and tailoring of treatment in cervical cancer. We extracted whole-volume radiomic texture features from 124 manually segmented tumors and performed unsupervised clustering yielding two distinct clusters. Overlapping clinicopathologic, genomic (whole exome sequencing, n=61), transcriptomic (L1000 arrays, n= 65) and molecular biomarker (n=82) data were applied to characterize the clusters. Independent of tumor size parameters, patients in cluster II had significantly reduced disease-specific survival as compared to those in cluster I (p&amp;gt;0.001), also within squamous cell carcinomas (n=96, p&amp;lt;0.001). Cluster II associated with high age (p=0.02), high FIGO-2009 stage (p&amp;lt;0.001), high BMI (p=0.03) and PR negative tumors (p=0.004). Distinct mutational and copy-number profiles were detected for the two clusters. By gene set enrichment analyses, gene sets associated to immune activation were enriched in cluster I tumors, whilst gene sets associated with oxidative phosphorylation and epithelial to mesenchymal transition associated to cluster II tumors. This study links radiomic signatures to distinct genomic profiles that may potentially aid in prognostication and tailoring of treatments in cervical cancer patients. Citation Format: Mari Kyllesø Halle, Erlend Hodneland, Erling Hoivik, Kari Wagner-Larsen, Njål G. Lura, Julie Dybvik, David Forsse, Bjørn I. Bertelsen, Camilla Krakstad, Ingfrid S. Haldorsen, Olivera Bozickovic, Kathrine Woie. Radiomic profiles revealing targets for therapy in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 513.